Stress dysregulation of drug reward pathways, and the transition to drug dependence
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This review provides a neuroadaptive perspective regarding the role of the hormonal and brain stress systems in drug addiction with a focus on the changes that occur during the transition from limited access to drugs to long-term compulsive use of drugs. A dramatic escalation in drug intake with extended access to drug self-administration is characterized by a dysregulation of brain reward pathways. Hormonal studies using an experimenter-administered cocaine binge model and an escalation self-administration model have revealed large increases in ACTH and corticosterone in rats during an acute binge with attenuation during the chronic binge stage and a reactivation of the hypothalamic-pituitary-adrenal axis during acute withdrawal. The activation of the hypothalamic-pituitary-adrenal axis with cocaine appears to depend on feed-forward activation of the mesolimbic dopamine system. At the same time, escalation in drug intake with either extended access or dependence-induction produces an activation of the brain stress system's corticotropin-releasing factor outside of the hypothalamus in the extended amygdala, which is particularly evident during acute withdrawal. A model of the role of different levels of hormonal/brain stress activation in addiction is presented that has heuristic value for understanding individual vulnerability to drug dependence and novel treatments for the disorder.
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Chronic nicotine exposure causes neuroadaptations that produce widespread changes in brain neurotransmission, promoting and sustaining tobacco use.
“The neuroadaptations arising from chronic nicotine exposure cause widespread alterations in brain neurotransmission that promote and sustain the use of tobacco [21–24].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [21]
In drug addiction, CRF is primarily involved in withdrawal from drugs of abuse.
“In drug addiction, CRF is primarily involved in withdrawal from drugs of abuse (Koob and Kreek 2007; Koob 2008).”
From The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction (2012) · cites this paper as Koob and Kreek 2007
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“Acute withdrawal from many drugs elevates corticosterone and corticotropin-releasing factor (CRF) (Koob 2008, Koob & Kreek 2007).”
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Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development
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Addiction and Stress: An Allostatic View
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“In drug addiction, CRF is primarily involved in withdrawal from drugs of abuse (Koob and Kreek 2007; Koob 2008).”
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Development of pharmacotherapies for drug addiction: a Rosetta stone approach
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Reactivity to laboratory stress provocation predicts relapse to cocaine
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Candidate genes for cannabis use disorders: findings, challenges and directions.
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Making a bad thing worse: adverse effects of stress on drug addiction
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Epigenetics of drug abuse: predisposition or response
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Existing and future drugs for the treatment of the dark side of addiction
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Role of the Astroglial Glutamate Exchanger xCT in Ventral Hippocampus in Resilience to Stress
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Histone acetylation in drug addiction
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Stress–response pathways are altered in the hippocampus of chronic alcoholics
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Influence of Neuronal Nicotinic Receptors over Nicotine Addiction and Withdrawal
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Stress-Induced Potentiation of Cocaine Reward: A Role for CRFR1 and CREB
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- Authors
- Koob, & Kreek, M. J.
- Affiliations
- Scripps Research Institute (US)
- Venue
- American Journal of Psychiatry
- Published
- 2007-08
- Volume
- 164
- Issue
- 8
- Pages
- 1149-1159
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC2837343
- OpenAlex
- W2166133075
- Cited by
- 868
- References
- 85
- Citations by year
- 2026: 7 · 2025: 19 · 2024: 16 · 2023: 25 · 2022: 31 · 2021: 38 · 2020: 91 · 2019: 43 · 2018: 53 · 2017: 44 · 2016: 42 · 2015: 43 · 2014: 56 · 2013: 62 · 2012: 72
- FWCI
- 4.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R01AA008459, AA-06420, AA-08459, P50AA006420, R37AA008459, P60AA006420)
- National Institute of Mental Health (MH076537, R01MH076537)
- National Institute on Drug Abuse (DA-00049, DA04043, DA04398, P50DA005130, K05DA000049, DA 05130, P60DA005130, R01DA004398, R01DA004043)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 26741, P01DK026741)
- National Center for Research Resources (RR024143, UL1RR024143)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- drug addiction, stress, hypothalamic-pituitary-adrenal axis, mesolimbic dopamine system, corticotropin-releasing factor, extended amygdala, withdrawal, ACTH, corticosterone, reward pathways, individual susceptibility
- MeSH terms
- Animals, Brain, Corticotropin-Releasing Hormone, Disease Models, Animal, Electrodes, Implanted, Hydrocortisone, Hypothalamus, Models, Neurological, Prolactin, Reinforcement, Psychology, Reward, Self Administration, Illicit Drugs, Stress, Physiological, Behavior, Addictive, Substance-Related Disorders, Rats
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